rs4732516

Positions:

• chr7-75984764-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001395413.1(POR):​c.1058-13C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.935 in 1,611,828 control chromosomes in the GnomAD database, including 710,378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.85 (57007 hom., cov: 33)
  • Exomes 𝑓: 0.94 (653371 hom.)
• Consequence: POR NM_001395413.1 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.76

Genes affected

POR (HGNC:9208): (cytochrome p450 oxidoreductase) This gene encodes an endoplasmic reticulum membrane oxidoreductase that is essential for multiple metabolic processes, including reactions catalyzed by cytochrome P450 proteins for metabolism of steroid hormones, drugs and xenobiotics. The encoded protein has a flavin adenine dinucleotide (FAD)-binding domain and a flavodoxin-like domain which bind two cofactors, FAD and FMN, that allow it to donate electrons directly from NADPH to all microsomal P450 enzymes. Mutations in this gene cause a complex set of disorders, including apparent combined P450C17 and P450C21 deficiency, amenorrhea and disordered steroidogenesis, congenital adrenal hyperplasia and Antley-Bixler syndrome, that resemble those caused by defects in steroid metabolizing enzymes such as aromatase, 21-hydroxylase, and 17 alpha-hydroxylase. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 7-75984764-C-G is Benign according to our data. Variant chr7-75984764-C-G is described in ClinVar as [Benign]. Clinvar id is 138789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-75984764-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.957 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POR	NM_001395413.1	c.1058-13C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000461988.6	NP_001382342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POR	ENST00000461988.6	c.1058-13C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001395413.1	ENSP00000419970	P4

Frequencies

GnomAD3 genomes AF: 0.852 AC: 129552 AN: 152008 Hom.: 56976 Cov.: 33

Gnomad AFR AF: 0.610

Gnomad AMI AF: 0.923

Gnomad AMR AF: 0.871

Gnomad ASJ AF: 0.973

Gnomad EAS AF: 0.855

Gnomad SAS AF: 0.919

Gnomad FIN AF: 0.978

Gnomad MID AF: 0.934

Gnomad NFE AF: 0.963

Gnomad OTH AF: 0.878

GnomAD3 exomes AF: 0.911 AC: 225464 AN: 247390 Hom.: 103873 AF XY: 0.921 AC XY: 124107 AN XY: 134822

Gnomad AFR exome AF: 0.602

Gnomad AMR exome AF: 0.840

Gnomad ASJ exome AF: 0.975

Gnomad EAS exome AF: 0.853

Gnomad SAS exome AF: 0.922

Gnomad FIN exome AF: 0.977

Gnomad NFE exome AF: 0.963

Gnomad OTH exome AF: 0.933

GnomAD4 exome AF: 0.944 AC: 1377896 AN: 1459702 Hom.: 653371 Cov.: 47 AF XY: 0.945 AC XY: 686189 AN XY: 726174

Gnomad4 AFR exome AF: 0.596

Gnomad4 AMR exome AF: 0.848

Gnomad4 ASJ exome AF: 0.974

Gnomad4 EAS exome AF: 0.862

Gnomad4 SAS exome AF: 0.920

Gnomad4 FIN exome AF: 0.975

Gnomad4 NFE exome AF: 0.962

Gnomad4 OTH exome AF: 0.924

GnomAD4 genome AF: 0.852 AC: 129635 AN: 152126 Hom.: 57007 Cov.: 33 AF XY: 0.854 AC XY: 63476 AN XY: 74364

Gnomad4 AFR AF: 0.610

Gnomad4 AMR AF: 0.871

Gnomad4 ASJ AF: 0.973

Gnomad4 EAS AF: 0.855

Gnomad4 SAS AF: 0.919

Gnomad4 FIN AF: 0.978

Gnomad4 NFE AF: 0.963

Gnomad4 OTH AF: 0.878

Alfa AF: 0.916 Hom.: 11938

Bravo AF: 0.832

Asia WGS AF: 0.859 AC: 2988 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Benign:1

Benign, criteria provided, single submitter

case-control

Pecori Giraldi Lab, University of Milan

-

This variant is intronic -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.22
DANN	Benign	0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4732516; hg19: chr7-75614082;